A2a ADENOSINE RECEPTOR IN REMOTE LV DYSFUNCTION POST-MI

描述(由申请人提供)： A2A腺苷受体(A2AAR)的激动剂是已知的血管扩张剂 在相当低的剂量下也能抑制炎症。激活 A2AAR通过以下途径减轻心肌梗死后再灌注损伤 抑制白细胞活化、内皮细胞黏附和中性粒细胞 积累。不仅梗死区的收缩功能作为一种 心肌梗死的结果，但最近的证据表明，细胞因子的级联 心肌梗死引发的精细加工也会导致远程患者的收缩功能障碍 从未发生缺血的左心室(LV)区域。我们假设 A2AAR的抗炎特性可以用来 大面积心肌梗死后早期保留收缩功能。我们建议，整个 使用一套互补的药理学和遗传学的动物实验 方法将不仅阐明A2AARs的抗炎作用 这一设置，也将确定一种有效的治疗方案。在……里面 初步研究，我们使用了一种再灌流心肌梗死和心脏的小鼠模型 磁共振成像(MRI)显示A2AAR明显激活 改善心肌梗死后第一天的远程左心室功能。在建议的研究中， A2AAR在远期左心功能障碍中的抗炎作用将是 用特定的药理学试剂阐明，基因操纵的小鼠 和骨髓嵌合体。将使用跨学科的方法 免疫学、放射学、心脏生理学、病理学、细胞 生物学和分子遗传学。具体目的是：1)阐明 炎症在大面积心肌梗死后早期远期左心功能障碍中的作用。在……里面 初步研究，我们的实验室已经表明，一种高度选择性的激动剂 A2AAR(ATL146e)在第一天增强远程LV的收缩功能 心肌梗死后。我们推测A2AAR活化的抗炎作用 对这种有益的影响负有责任。2)确定 利用A2AAR基因敲除小鼠研究远程区左心功能障碍的内源性腺苷。 我们假设A2AAR的激活由内源性腺苷调节 心肌梗死后早期远端左室收缩功能。因此，偏远地区LV A2AAR基因敲除小鼠的功能障碍应该比同源基因小鼠更严重 野性的。3)确定髓系在远区LV中的作用 使用骨髓嵌合体的功能障碍。我们假设这个有益的 ATL146e对远区性左心功能障碍的影响 髓系细胞。如果是这样的话，将野生型骨髓移植到受辐射的 A2AAR基因敲除小鼠应恢复野生型表型。4)定义 A2AAR特异性激活对大鼠心肌基因表达的影响 心肌梗死后心脏的转录图谱分析。我们假设中央银行 细胞因子基因激活在远期左心功能不全中的重要性 通过比较假手术组、脑梗塞组和脑梗死组的基因表达谱来阐明 和ATL146e治疗的心脏。

DESCRIPTION (provided by applicant): Agonists of the A2A adenosine receptor (A2AAR) are known vasodilators that also inhibit inflammation at substantially lower doses. Activation of the A2AAR attenuates reperfusion injury after myocardial infarction (MI) by inhibiting leukocyte activation, endothelial adhesion and neutrophil accumulation. Not only is contractile function lost in the infarct zone as a result of MI, but recent evidence indicates that the cascade of cytokine elaboration initiated by MI also induces contractile dysfunction in remote zones of the left ventricle (LV) that were never made ischemic. We hypothesize that the anti-inflammatory properties of the A2AAR can be exploited to preserve contractile function early after large MI. We propose that whole animal experiments employing a complementary set of pharmacologic and genetic approaches will not only elucidate the anti-inflammatory role of A2AARs in this setting, but will also identify an effective treatment regimen. In preliminary studies, we have used a mouse model of reperfused MI and cardiac magnetic resonance imaging (MRI) to demonstrate that A2AAR activation markedly improves remote LV function on Day 1 after MI. In the proposed studies, the anti-inflammatory role of the A2AAR in remote LV dysfunction will be elucidated using specific pharmacologic agents, genetically-manipulated mice and bone marrow chimeras. A multidisciplinary approach will be used that spans the fields of immunology, radiology, cardiac physiology, pathology, cell biology and molecular genetics. The specific aims are to: 1) Elucidate the role of inflammation in remote LV dysfunction early after large MI. In preliminary studies, our lab has shown that a highly-selective agonist of the A2AAR (ATL146e) enhances contractile function in the remote LV on Day 1 post-MI. We hypothesize that the anti-inflammatory actions of A2AAR activation are responsible for this beneficial effect. 2) Determine the role of endogenous adenosine in remote zone LV dysfunction using A2AAR knock-out mice. We hypothesize that the activation of A2AAR by endogenous adenosine modulates contractile function in the remote LV early after MI. Thus remote zone LV dysfunction should be more severe in A2AAR knock-out mice than in congenic wild-types. 3) Determine the role of the myeloid lineage in remote zone LV dysfunction using bone marrow chimeras. We hypothesize that the beneficial effect of ATL146e on remote zone LV dysfunction is derived from its actions on myeloid cells. If so, transplantation of wild-type bone marrow into irradiated A2AAR knockout mice should restore the wild-type phenotype. 4) Define the impact of specific A2AAR activation on myocardial gene expression in the post-MI heart using transcriptional profiling. We hypothesize that the central importance of cytokine gene activation in remote LV dysfunction can be elucidated by comparing mRNA expression profiles from sham-operated, infarcted and ATL146e-treated hearts.